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Abstract

We present a novel, general class of disease progression models for Huntington's disease (HD), a neurodegenerative disease caused by a cytosine-adenine-guanine (CAG) triplet repeat expansion on the huntingtin gene. Models are fit to a selection of structural imaging markers from the TRACK 36-month database. The models are of mixed effects type and should be useful in predicting any continuous marker of HD state as a function of age and CAG length (the genetic factor that drives HD pathology). The effects of age and CAG length are modeled using flexible regression splines. Variability not accounted for by age, CAG length, or covariates is modeled using terms that represent measurement error, population variability (random slopes/intercepts), and variability due to the dynamics of the disease process (random walk terms). A Kalman filter is used to estimate variances of the random walk terms.

Simulated trajectories for striatum (Iowa): Huntington's disease (HD) participants trajectories are simulated under the Base, Random Slope (RS), Random Walk (RW), and Full models in the population of HD participants. The simulations are based on 50 replicates and assume cytosine‐adenine‐guanine (CAG) lengths of 42. Trajectories are simulated and plotted for ages starting at 18 years and ending at 70 years. Simulated trajectories are for a male equally likely to be selected from any of the four sites.